The overall goal of this project is to identify genes which are differentially expressed in alcoholics as compared to non-alcoholics. This will be accomplished by collecting autopsy material from individuals extensively characterized for drinking history, other pathologies, drug and tobacco use, brain histology, and genotype. In addition to the existing Australian Brain Bank, one of the most extensive for alcoholic cases available in the world, emphasis will be placed on collecting additional cases with specific attributes, such as abstinent alcoholics. Gene expression will be measured in frontal and motor cortex by microarrays that simultaneously measure levels of up 7000 expressed genes from a single sample of brain RNA. Our preliminary results demonstrate the feasibility of these approaches and suggest changes in gene expression consistent with published studies as well as changes in novel genes. About 30 genes of particular merit and interest will be selected for detailed analysis with a particular emphasis on correlating changes in mRNA expression to protein expression. Gene expression in the alcoholic brain may be changed due to predisposing factors (susceptibility genes), as a consequence of chronic ethanol exposure (alcohol responsive genes) or as a consequence of alcoholic neuropathology, other pathology (e.g., cirrhosis) or co-morbidity (e.g., tobacco use). We propose that careful case selection for analysis of gene expression will allow us to distinguish among (at least some of) these possibilities.